Significant pain in cases of spinal cord injury (SCI) or traumatic brain injury (TBI) is quite common, with an estimated 52-58% of TBI patients reporting chronic pain (Sherman et al. 2006). Headache is the most common symptom, but symptoms suggestive of neuropathic pain are also common, sometimes extending into the neck and regions of the shoulder and back (Uomoto et al. 1993). In this study, pain after TBI occurred in more than one area of the body in 60% of patients. Similarly, in spinal cord injury, around 40% of patients develop persistent neuropathic pain (Baastrup & Finnerup 2008; Yezierski 2005). Neuropathic pain is characterized by spontaneous persistent pain and a range of abnormally-evoked responses, such as allodynia (pain evoked by non-noxious stimuli), and hyperalgesia (an enhanced response to noxious stimuli).
A very common cause of CNS-mediated responses contributing to neuropathic pain is cervical or lumbar nerve root injury (radiculopathy), often a result of whiplash or disc herniation. Nerve roots sit at the junction of the central and peripheral nervous systems (PNS) and contain elements of both nervous systems (Fraher et al. 1987). Both radiculopathic and neuropathic injuries affect cellular mechanisms both locally at the site of injury (that is, the nerve root or nerve), and centrally in the spinal cord. Moreover, the CNS (brain and spinal cord) has been shown to mount cellular and molecular cascades in response to neuropathic and radiculopathic injuries that reflect a perceived injury to the CNS (Hashizume et al. 2000; DeLeo & Yezierski 2001; DeLeo & Winkelstein 2002; Watkins & Maier 2005). Therefore, CNS-mediated pain includes pain with injury originating in the CNS, although it can include pain from injuries that originate in the PNS.
There is a substantial literature on possible interventions, including pharmacological (Basstrup & Finnerup 2008) and physical (acupuncture, heat, electrical) treatments (Kumar et al. 2007). However, all these methods have proved inadequate, and no safe, effective method to treat pain after CNS-mediated responses to neuronal injury has been developed.
Neuropathic pain after CNS injury can have different causes, but activation of microglia and the resulting NO production, and release of pro-inflammatory cytokines is a common mechanism (Huselbosch 2008; Rothman et al 2009b). In addition to its pro-coagulant properties, activation of microglia is one of the many properties of mammalian thrombin, a multifunctional serine protease (Weinstein et al. 2008). Since activation of microglia predicts neuropathic pain, the exposure of CNS tissue to thrombin is contraindicated although it is inevitably produced as a result of blood coagulation subsequent to traumatic injury. Xue et al. (2006) show that thrombin from intracerebral injection of autologous blood in mice produced significant brain damage. Further evidence of thrombin's neurotoxicity on CNS tissue is the neuroprotective effect of thrombin inhibitors (Festoff et al. 2004).
The primary structure of thrombins from various species is highly conserved (Banfield & MacGillivray, 1992). Michaud et al. (2002) compared human and salmon thrombin, and found that they were nearly identical in polymerizing fibrinogen and activating Factor XIII, and similar but not identical in stimulating human platelets. They differed in the greater activity of salmon thrombin at low pH and high salt environments. Sawyer et al. (1999), Wang et al. (2000), and Laidmae et al. (2006) demonstrated the similarity of salmon and mammalian-derived thrombin and fibrinogen as fibrin sealants. When combined with fibrinogen, mammalian thrombin appeared safe for use in the rat CNS (Petter-Puchner et al. 2007), but there was no attenuation of the inflammatory response, and its capability to cause pain was unexamined. Fibrin gels composed of salmon fibrinogen and either human or salmon thrombin were equally effective in enhancing neurite outgrowth from mammalian neurons, and Ju et al. (2007) identified salmon fibrinogen, which differs in amino acid sequence and glycosolation from mammalian fibrinogen, as the beneficial component.